PROJECT SUMMARY The toxic and carcinogenic exposures associated with e-cigarette use, and the potential long-term health outcomes are not well characterized. While the levels of most tobacco-related harmful constituents are generally much lower in e-cigarettes than in cigarette smoke, and the limited literature on biomarker-based human exposures generally supports these findings, the number of chemical constituents identified in e- cigarette aerosol continues to grow. Many of these newly identified constituents can potentially cause oxidative stress and inflammation, and result in DNA damage ? effects that are strongly implicated in the etiology of chronic diseases, including cancer and cardiovascular disease. In addition, our recent data indicate that the potent oral and esophageal carcinogen N?-nitrosonornicotine (NNN), which is present only in trace levels in e- cigarettes, can be formed in saliva of e-cigarette users. Better characterization of toxic and carcinogenic exposures and related effects in e-cigarette users will help to assess the potential long-term health effects of e- cigarette use. In this study, we will recruit smokers of regular cigarettes and will randomized to the following experimental conditions for 8 weeks: 1) complete switching from smoking to the Standard Research E- cigarette (SREC) developed by the National Institute of Drug Abuse (N=50); 2) complete switching from smoking to an oral medicinal nicotine product, such as nicotine gum or lozenge (N=50); and 3) continued smoking of usual brand cigarettes as a control group (N=25). Study participants will be assessed at baseline and weeks 1, 2, 4, 6, and 8 for smoking abstinence, SREC use patterns, topography, and subjective measures. We will incentivize participants assigned to SREC and medicinal nicotine to encourage complete abstinence from smoking. Biomarkers of exposure and effect will be assessed at baseline and weeks 4 and 8. Our specific aims are: (1) To analyze a panel of exposure biomarkers in smokers assigned to SREC and compare the exposure profiles against medicinal nicotine products and usual brand cigarettes. The biomarkers will include TNE, NNAL, PheT, and mercapturic acids HMPMA, 2-HPMA, and 3-HPMA. (2) To compare formaldehyde-DNA adducts in oral cells, 8-oxo-dG in DNA from leukocytes, a comprehensive panel of circulating cytokines and chemokines, and the urinary biomarkers of oxidative damage and inflammation 8-iso- PGF-2? and PGEM across the groups. (3) To analyze salivary NNN and oral cell HPB-releasing DNA adducts in smokers who completely switch to SREC and compare those who switch to medicinal nicotine products or continue smoking usual brand cigarettes. Collectively, the results of this study will provide important data on chemical exposures and associated effects in smokers switching to SREC, contributing to better understanding of the long-term health effects that may be associated with e-cigarette use.